Given the proven potential for uncovering novel biology and for drug discovery by studying animals that have evolved extreme biology to survive, we have recently employed the post-prandial Burmese python as an animal model to discover novel pathways of beneficial cardiac adaptation. An infrequent feeder, the Burmese python exhibits a ~40-fold increase in overall metabolic rate and a 160-fold increase in plasma triglycerides within a day of eating a meal that can equal its body mass.1,2 This extreme metabolic demand activates potent, rapid and reversible organ growth, including physiologic cardiac hypertrophy.1,3 We found that post-prandial cardiac hypertrophy is accompanied by cardioprotective mechanisms that activate beneficial changes in gene expression and, despite very high circulating triglycerides, prevent cardiac lipid accumulation. Instead, the heart increases expression and activity of genes involved in lipid handling, mitochondrial oxidative capacity, and free radical scavenging.3 Importantly, we identified a novel combination of 3 fatty acids (FAs) (myristic [C14:0; 40 M], palmitic [C16:0;100 M] and palmitoleic [C16:1; 7.5 M] acids) in post-prandial python plasma that when administered to either pythons or mice promotes beneficial cardiac adaptation3 with no signs of pathologic lipid signaling. This appears to be independent of PPAR signaling; these and other data lead us to believe that this pathway is novel. Moreover, we found that an aqua-glyceroporin gene, aquaporin 7 (AQP7), is the most potently activated gene in rat cardiac myocytes treated with these FAs and its expression is upregulated in hearts of FA-treated mice. We have made cardiac myocyte-specific AQP7 null mice and have found that they have an exaggerated pathological response to adrenergic stimulation. These data, in conjunction with bi-directional responses of the AQP7 gene in exercise and disease, suggest that AQP7 may be mediating some of the cardioprotective mechanisms described above. Based on these data, the goals of this project are three-fold. First, we will elucidate cardioprotective mechanisms utilized by the python and translate them to mammals. Second, many aspects of the python post- prandial cardiac responses resemble the beneficial mammalian cardiac response to exercise. Therefore, we will explore the preventive and therapeutic potential of the FAs before or after a pathologic cardiac stimulus, respectively. We will define the mechanisms underlying the ability of these FAs to modify disease. Third, we will define the mechanisms by which the python heart undergoes regression subsequent to hypertrophic growth. The results of these proposed experiments should suggest novel signaling pathways that may lead to therapeutics for cardiovascular disease.